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Objective To find novel lead compounds as p53-MDM2 inhibitors by drug repurposing strategy. Methods The p53-MDM2 inhibitory activities of compounds were determined by FP and western blotting. MTT method was used to determine the in-vitro antitumor activities. The metabolites in human liver microsomes were tested. Results Bepridil showed excellent in-vitro anti-tumor activity and strong p53-MDM2 protein binding inhibitory activity, which can significantly reduce the expression of MDM2 protein in a dose-dependent manner. The metabolites in human liver microsomes are mainly benzene ring hydroxyl mono-oxidation metabolites. Conclusion Bepridil can be used as a lead compound for p53-MDM2 protein binding small molecule inhibitors for subsequent structural optimization design studies.
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Object To observe the protective effects of rehmannia root extract (Reh) on mitochondrial respiratory function in hypoxia rat. Methods Rat was killed rapidly and the body was put at room temperatare for global ischemia of 15 min. Treatment of po Reh 2 and 4 g/kg was started 2 h before hypoxia. The mitochondrial respiratory parameter of myocardium, brain and kidney was measured by oxygen electrode method. The protective effect of Reh on mitochondrion was observed in 2h po. Bepridil (Bep), an Ca 2+ channel blocker, ip 5 mg/kg 30 min prior to hypoxia served as positive control. Results In myocardium and kidney, hypoxia injury was showed similar, ST 3 and RCI value was increased as compared with the control group in a dose dependent manner, showing a selective stronger protection on renal mitochondrial than that on heart and brain. Conclusion Reh is effective in protecting metochondrial respiratory function in heart, brain and kidney from hypoxia and with the most potent effect on kidney.
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Bepridil hydrochloride(Bep) hydrochloride is a new , long - acting antianginal and antiarrhythmic agent. Through the observation of ∑ST.NST.and NQ of ECG or nitro blue tetrazolium chloride staining, we studied the effect of Bep on liga-tion of the left coronary artery in rabbits and the myocardial ischemia induced by isopre-naline in rats. The results showed that in the groups treated with Hep andpropranolol theisoelectric level was facilitated. ∑ST.NST, NQ, thecreatine phosphokinase values and the weight percentage of infarcted myocardium were decreased. The myocardial ischemic injury was decreased by histopathological stud-
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The effects of bepridil, ni-modipine and nicardipine on the activity of CaM - dependent protein kinase Ⅱ from mouse cerebrum were studied in vitro. Tt was found that bepridil significantly inhibitied the activity of CaM - PK Ⅱ with an IC50 value of 0. 3 mmol ? L-1. but nimodipine and nicardipine did not basi-cally influence the activity of the enzyme. The experimental results showed that the inhibitory effect of bepridil on the activity of CaM - PK Ⅱ was an antagonistic action of bepridil to CaM.
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Bepridil (10mg ? kg-1) iv elevated the threshold dose of ouabain (15ug ? min-1 iv) in guinea-pig and aconitine (10?g ? kg-1 ? min-1 iv) in rat induced ventricular extrasystole, ventricular tachycardia, ventricular fibrillation and cardiac arrest. It shortened the duration of arrhythmia elicitde by Adr (50ug ? Kg-1 iv) in conscious rabbits and by BaCl2 (3mg ? kg-1 iv) in rats. It is also effective in preventing reperfusion-induced arrhythmias in aneasthetized rats.
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The inhibitory effects of cicletanine (Cic) and bepridil (Bep) on norepinephrine (NE)-and KCl-induced contractions were studied in isolated thoracic aorta rings of male Sprague-Dowley rats. It was found that Cic had a more potent effect on NE-induced contraction than on KCHnduced contraction. In. contrast, Bep had a more potent action on KCHnduced contraction. When the aorta rings were incubated with Cic and Bep, a potentialized inhibitory effect was observed on KCh but not NE-induced contractions. These effects were independent of the presence of endothelium. The results suggest that Cic and Bep have different action sites and properties on vascular smooth muscles.